Rapid Spread of Mutant Alleles in Worldwide SARS-CoV-2 Strains Revealed by Genome-Wide Single Nucleotide Polymorphism and Variation Analysis

Abstract

The novel coronavirus (SARS-CoV-2) has become a pandemic and is threatening human health globally. Here, we report 9 newly evolved SARS-CoV-2 single nucleotide polymorphism (SNP) alleles those underwent a rapid increase (7 cases) or decrease (2 cases) in their frequency for 30% ∼ 80% in the initial four months, which are further confirmed by intra-host single nucleotide variation (iSNV) analysis using raw sequence data including 8217 samples. The 9 SNPs are mostly (8/9) located in the coding region and are mainly (6/9) nonsynonymous substitutions. The 9 SNPs show a complete linkage in SNP pairs and belong to 3 different linkage groups, named LG_1 to LG_3. Analyses in population genetics show signatures of adaptive selection towards the mutants in LG_1, but no signal of selection for LG_2. Population genetic analysis results on LG_3 show geological differentiation. Analyses on geographic COVID-19 cases and published clinical data provide evidence that the mutants in LG_1 and LG_3 benefit virus replication and those in LG_1 have a positive correlation with the disease severity in COVID-19 infected patients. The mutants in LG_2 show a bias towards mildness of the disease based on available public clinical data. Our findings may be instructive for epidemiological surveys and disease control of COVID-19 in the future.

Nucleocapsid mutation R203K/G204R increases the infectivity, fitness and virulence of SARS-CoV-2

“…These results demonstrated that the R203K/G204R mutation enhanced viral replication through increasing virion infectivity in primary human upper airway tissues. In consistent to our experimental results, we previously observed a negative correlation of R203/G204 IF with the cycle threshold for positive signal in E gene-based RT-PCR (Ct) 10 .…”

“…The increase in replication may lead to the increase of virulence and fitness in the end. Other high infectivity related mutations, such as D614G and N510Y, also showed association with the increased fitness and severity of diseases 9,10,33–35 . R203K/G204R is akin to predominance like D614G (Figure 1) and is shared by rapidly growing lineages, B.1.1.7 and P.1.…”

“…In our previous work, we observed the rapid spread of R203K/G204R in the initial four months after the pandemic of SARS-CoV-2 and predicted that the mutants possibly benefit virus replication based on statistics 10 . In this study, we not only validated the increase of infectivity by experiments, but also identified and validated the increase of virulence and fitness.…”

“…R203K/G204R is a co-occurring N mutation, growing rapidly and with potential association with the infectivity of virus 10 . This mutation carried by B.1.1.7 and P.1 referred above was identified with selection signatures by our previous work 10,24 .…”

“…R203K/G204R is a co-occurring N mutation, growing rapidly and with potential association with the infectivity of virus 10 . This mutation carried by B.1.1.7 and P.1 referred above was identified with selection signatures by our previous work 10,24 . We kept tracking the evolution of R203K/G204R based on all documented SARS-CoV-2 genome sequences monthly, and found this mutation has a second time rapid growth accompanied with the emergence of B.1.1.7 (Figure 1).…”